KR20200004573A - Pharmaceutical composition for treating depression and stress-associated diseases comprising oxazoloquinolinone derivatives - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating depression and stress-related diseases comprising, as an active component, an oxazolo-quinazoline derivative compound represented by chemical formula 1a or chemical formula 1b having antidepressant efficacy.

Description

Pharmaceutical composition for treating depression and stress-associated diseases comprising oxazoloquinolinone derivatives}

The present invention relates to a pharmaceutical composition for the prevention or treatment of depression and stress-related diseases comprising an oxazoloquinazoline derivative compound having antidepressant efficacy as an active ingredient.

In modern society, mental illness is on the rise, which is due to the increase of individual loneliness due to nuclear familyization, psychological stress from high divorce rate and fierce competition. Chronic psychological stress prevalent in modern society results in depression, which is why depression-related drugs in Western society are among the highest prescription rates among prescription drugs. The World Health Organization (WHO) estimates that by 2020, depression will be the most socially burdened disease in the United States and Western Europe. As urbanization accelerates in Korea, the gap between rich and poor and alienation are intensifying, leading to a sharp increase in the incidence of depression. Currently, Korea is one of the highest suicides among OECD countries.

There is no theory yet that fully explains the mechanism of depression and the mechanism of action of antidepressants, which are treatments for depression. However, in general, the lack of a monoamine-based neurotransmitter serotonin, norepinephrin, dopamine, etc. in the central nervous system synapses is most likely to cause depression. It is a hypothesis. Thus, current antidepressants also have a pharmacological action that increases the concentration of neurotransmitters in central serotonin or noradrenaline synapses. Antidepressants are largely tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), or selective serotonin reuptake inhibitors (SSRIs), depending on the mechanism of increasing neurotransmitter concentrations. Etc. are used a lot.

These conventional antidepressants often have a therapeutic response rate of about 50%, which is often insufficient, and some have severe side effects. Due to drug administration, the concentration of monoamine in the synapses increases immediately, but it usually takes about 4-6 weeks to improve symptoms such as improving depression. Tricyclic antidepressants such as imipramine and desipramine have severe side effects such as hypotension and cardiac dysfunction. Selective serotonin reuptake inhibitors, such as fluoxetine or sertraline, are the most widely used, causing nausea, gastrointestinal bleeding or sexual dysfunction. Therefore, there is an urgent need to develop new drugs that are more effective and have fewer side effects than existing antidepressants. In addition, at present, the economic and social effects of new drug development are enormous, but the development cost is enormous and it is not easy to develop.

Interleukin-33 (IL-33) is a congenital cytokine produced mainly by various stimuli in mucosal epithelial cells. The IL-33 receptor complex for IL-33 mediated signaling is a ligand, IL-33, a ligand conjugate. It is composed of ST2 (IL-1R4) and IL-1 receptor accessory protein (IL-1RAcP; IL-1R3), which is a signal carrier. Stimulation of IL-33 produces Th2 inflammatory cytokines and chemokines including IL-4, IL-5, IL-6, IL-13 and IL-8. When IL-33 binds, the IL-33 receptor complex is passed through sub-signals such as NF-kB and AP-1 via IL-1 receptor-associated kinase (IRAK), TNF receptor associated factor 6 (TRAF6) and / or MAPKs. Activate the molecules of the system.

Inflammatory processes are associated with the development of depressive disorders, and IL-33 expression is increased in the hypothalamus due to stress, especially with respect to the development of recurrent depressive disorders. 33 has been shown to play a major role and that IL-33 expression in central nervous system astrocytes plays an important regulator of major immune responses.

After all, TSLP and IL-33 are cytokines that play an important role in the expression of Th2 inflammatory cytokines and chemokines. It is expected that radical treatment of degenerative brain disease accompanied by inflammatory response may be possible.

Accordingly, the present invention contains an oxazoloquinolinone derivative and an effective ingredient that control the intracellular signal transduction by TSLP and IL-33, which is effective in the prevention or treatment of depression or stress-related diseases, and is pharmaceutically acceptable. To provide a pharmaceutical composition for the prevention or treatment of depression and stress-related diseases comprising a carrier.

In order to solve the above problems, the present invention comprises a oxazoloquinolinone derivative represented by the following [Formula 1a] or [Formula 1b] as an active ingredient, and depression and stress-related diseases comprising a pharmaceutically acceptable carrier. It provides a pharmaceutical composition for the prophylaxis or treatment of.

[Formula 1a]

[Formula 1b]

The structures of Formulas [1a] and [Formula 1b], specific substituents, and specific oxazoloquinolinone derivatives thereof will be described later.

The oxazoloquinolinone derivative compounds according to the present invention have an antidepressant effect to alleviate depression and stress-related behavior, and can be prevented or treated for various diseases related to depression and stress by using the pharmaceutical composition comprising the same.

1 is a view showing the results of behavioral analysis on the antidepressant efficacy in LPS-mediated depression animal model using the oxazoloquinolinone derivative according to the present invention, [Formula 10] (KB1518) treatment is LPS-injected C57BL / 6 It can be seen that reduced depression-related behavior of the mouse.
FIG. 1A is a schematic diagram showing an experimental procedure, FIG. 1B shows reduced immobility in TST test of mice treated with [Formula 10] (KB1518), and C and D of FIG. In comparison, mice administered KB1518 showed no difference in OFT (FIG. 1C), but no difference in immobility time in FST (left panel of FIG. 1D), but the swimming behavior to climb the wall Was significantly increased in KB1518 treated mice (FIG. 1D, right panel).

Hereinafter, the present invention will be described in more detail.

The inventors of the present invention after confirming that the oxazoloquinolinone derivatives represented by the following [Formula 1a] and [Formula 1b] effectively inhibit the binding between the cytokines TSLP and IL-33, such cytokines and receptors, The present invention was completed by confirming that treatment with oxazoloquinolinone derivatives can significantly alleviate depression and stress-related behavior in animals.

The present invention comprises an oxazolo quinolinone derivative represented by the following [Formula 1a] or [Formula 1b] as an active ingredient, a pharmaceutical composition for the prevention or treatment of depression and stress-related diseases comprising a pharmaceutically acceptable carrier It is about.

[Formula 1a]

[Formula 1b]

In [Formula 1a] and [Formula 1b],

R ₁ and R ₂ may be the same as or different from each other, and may each independently be an alkyl group having 1 to 10 carbon atoms, and any one selected from the following [Formula 1].

[Formula 1]

-Z-alkyl group

In [Formula 1], Z is a hetero atom selected from O, S or N, or-(CH ₂ ) _m- (wherein m is an integer of 0 to 5).

X and Y are each independently selected from hydrogen, halogen group, hydroxyl group, amino group, nitro group, cyano group, halogenated alkyl group having 1 to 10 carbon atoms, CO-R ', NHR', NR'R ', NHCOR' and COOR ' (Wherein R 'is an alkyl group having 1 to 10 carbon atoms).

p is an integer of 0-4, q is an integer of 0-5, and when said p and q are multiple, some X and some Y are each the same or different.

The oxazoloquinolinone derivatives represented by the above [Formula 1a] or [Formula 1b] are not limited thereto, but may be any one selected from the following [Formula 2] to [Formula 15]. .

[Formula 2] [Formula 3]

[Formula 4] [Formula 5]

[Formula 6] [Formula 7]

[Formula 8] [Formula 9]

[Formula 10] [Formula 11]

[Formula 12] [Formula 13]

[Formula 14] [Formula 15]

The oxazoloquinolinone derivatives according to the present invention can be prepared through a Sandmeyer reaction, a Suzuki-bonding and a Heck reaction under a palladium-catalyst, a nitro group reduction reaction, a cyclization reaction and a substitution reaction under basic conditions, for example. Various 2-aryloxazole-4-carboxylate derivatives can be synthesized using arylboronic acid substituted with ethyl 2-chlorooxazole-4-carboxylate obtained through Sandmeyer reaction using ethyl 2-aminooxazole-4-carboxylate as starting material. have. In addition, 2-aryl-5-aryloxazole-4-carboxylate derivatives having various substituents introduced therein may be prepared using 2-iodo-1-nitrobenzene substituted in the Heck reaction. After reducing the nitro group through a hydrogenation reaction, an oxazoloquinolinone derivative may be synthesized through an intramolecular reaction between an amine group and an ester group under basic conditions. Under basic conditions, various oxazoloquinolinone derivatives represented by the above [Formula 1a] or [Formula 1b] may be prepared by a substitution reaction with dialkylethyl bromide.

More specifically, the compounds of [Formula 2] to [Formula 13] may be prepared through the synthesis process as described below, and [1] may be represented by [oxazoloqui] represented by [Formula 1a] or [Formula 1b] according to the present invention. In the nolinone derivative, R ₁ and R ₂ are a flowchart illustrating a synthesis process of a compound having a methyl group, and [2] and [3] schematically illustrate a synthesis process of a compound having R ₁ and R ₂ as an ethyl group. It is a flow chart.

[One]

[2]

[3]

In addition, the pharmaceutical composition according to the present invention may be administered in the form of a complex preparation together with other drugs known for preventing or treating depression and various stress-related diseases, or may include other ingredients such as carriers, diluents, adjuvants and stabilizers, and the like. have.

In addition, the form of the composition according to the present invention may be variously selected depending on the mode to be administered, but is not limited thereto, for example, solid phases such as tablets, pills, powders, capsules, gels, ointments, fluids or suspensions, and the like. It may be in the form of a semi-solid or liquid dosage form, may be administered in a unit dosage form suitable for the precise administration of the dosage alone, orally or parenterally, and in the case of parenteral administration, intravenous, subcutaneous, It can be administered by intramuscular injection.

In addition, the compositions may include, depending on the desired formulation, a pharmaceutically acceptable carrier, diluent, adjuvant, stabilizer, defined as an aqueous-based carrier commonly used in formulating pharmaceutical compositions for human administration.

Carrier means a substance that facilitates the addition of the compound into cells or tissues, for example, as commonly used in the preparation, carbohydrate compounds (eg lactose, amylose, dextrose, water) Cross, sorbitol, mannitol, starch, cellulose, etc.), acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, salt solution, alcohol, arabian Rubber, vegetable oils (e.g. corn oil, cotton seed oil, soy milk, olive oil, coconut oil), polyethylene glycol, methyl cellulose, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate and mineral oil However, the present invention is not limited thereto. Diluent is defined as a substance that not only stabilizes the biologically active form of a compound of interest, but also is diluted in water to dissolve the compound. Examples of diluents include distilled water, physiological saline, Ringer's solution, glucose solution, and Hank's solution and the like. Stabilizers can be selected from the group consisting of proteins, sugars, buffers and mixtures thereof. In addition to the above components, lubricants, wetting agents, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives and the like, but also not limited thereto.

In addition, an effective amount of other components such as carriers, diluents, adjuvants and stabilizers and the like is an amount effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, etc. of the component.

In the present specification, "prevention" has not been diagnosed as having a disease or a disease, but means inhibiting the occurrence of such a disease or a disease, "treatment" refers to the inhibition of the development of a disease or a disease, a disease or a disease It is meant to include the alleviation and elimination of diseases or diseases.

In addition, "contains as an active ingredient" means that the ingredient is included in an amount necessary or sufficient to realize a desired biological effect. In practical applications, the determination of the amount to be included as an active ingredient is an amount for treating a subject disease, and may be determined in consideration of matters that do not cause other toxicity, for example, the disease or condition being treated, the form of the composition to be administered, It may vary depending on various factors such as the size of the subject or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of an individual composition without undue experimentation.

In addition, "pharmaceutically acceptable" means a property that does not impair the biological activity and physical properties of the compound.

On the other hand, the "stress-related disease", first stress is known to increase the function of the pituitary-adrenal system, the sympathetic nervous system, causing hormone secretion and various symptoms appear.

In particular, exposure to chronic stress causes atrophy and damage of the hippocampus responsible for memory and learning, which can lead to various mental disorders (depression, post-traumatic stress disorder, etc.). In addition, degenerative brain diseases such as Alzheimer's disease and Parkinson's disease may be related to stress and brain inflammatory response as well as depression.

Other terms and abbreviations used herein may be interpreted as meanings commonly understood by those skilled in the art to which the present invention belongs unless otherwise defined.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples are provided only to assist the understanding of the present invention and do not limit the scope of the present invention.

Synthesis Example  : According to the present invention Oxazoloquinolinone  Synthesis of Derivatives

Synthesis process of the compound According to the flow chart [1], [2], [3] oxazoloquinolinone derivatives of [Formula 2] to [Formula 15] according to the present invention were synthesized by the following method.

(a) Intermediate Ethyl 2- chlorooxazole -4- carboxylate  (21)

Ethyl 2-aminooxazole-4-carboxylate (468 mg, 3 mmol) was added to t-butylnitrite (540 μl, 0.45 mmol), copper chloride (600 mg, 4.5 mmol) and acetonitrile (22 ml). Add at 60 ° C. and heat the mixture at 80 ° C. for 1 h. After cooling the mixture was partitioned in dichloromethane, ice, hydrochloric acid, the aqueous layer was further extracted with dichloromethane and the organics were washed with brine, dried (MgSO ₄ ) and evaporated.

The product was purified by silica gel column chromatography (hexane / Et 2 O, 7: 1 to 4: 1, v / v) to give product 21 as a white fluffy white solid (338 mg, 64%).

R _f = 0.38 (hexane / Et ₂ O = 2: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.20 (s, 1H), 4.40 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 6.9 Hz, 3H). LRMS (ESI) m / z 176.1 [M + H] ⁺ .

(b) Suzuki Reactions  Through intermediate ethyl 2- aryloxazole -4- carboxylate  Derivative synthesis method

(1) ethyl 2-chlorooxazole-4-carboxylate (257 mg, 1.47 mmol), 4-fluorophenylboronic acid (252 mg, 1.8 mmol, 1.2 eq.) And tetrakis (triphenylphosphine) Palladium (0) (85 mg, 0.07 mmol, 0.05 eq.) Was dissolved in toluene (20 mL) and 2 M potassium carbonate solution (2.0 mL, 4.0 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was reflected for 1 hour with stirring, cooled to room temperature, the reaction mixture was partitioned between ethyl acetate and 2M sodium hydroxide solution, and the aqueous layer was washed twice more with ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo.

The product was purified by silica gel column chromatography (hexane / Et 2 O, 5: 1 to 3: 1, v / v) to give product 22b as a white solid (250 mg, 73%) in the shape of fluffy.

R _f = 0.30 (hexane / Et ₂ O = 2: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.25 (s, 1H), 8.11 (dd, J = 5.4 and 8.9 Hz, 2H), 7.16 (t, J = 9.0 Hz, 2H), 4.42 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.2, 162.9, 161.7, 161.3, 143.7, 134.7, 129.2, 129.1, 122.8, 122.8, 116.3, 116.1, 116.0, 115.7, 61.4, 14.3. LRMS (ESI) m / z 257.8 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₁₂ H ₁₀ FNO ₃ Na ⁺ [M + Na] ⁺ : 258.0537; found: 258.0528.

(2) Ethyl 2- phenyloxazole -4- carboxylate  (22a)

R _f = 0.30 (hexane / Et ₂ O = 2: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.28 (s, 1H), 8.12 (dd, J = 2.1 and 7.2 Hz, 2H), 7.16 (dd, J = 1.8 and 5.3 Hz, 2H), 4.43 (q , J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). LRMS (ESI) m / z 218.0 [M + H] ⁺ and 239.9 [M + Na] ⁺ .

(3) Ethyl 2- (4- chlorophenyl ) oxazole -4- carboxylate  (22c)

R _f = 0.38 (hexane / Et ₂ O = 2: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.27 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 4.43 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). LRMS (ESI) m / z 251.8 [M + H] ⁺ and 273.8 [M + Na] ⁺ .

(4) Ethyl 2- (4- ( trifluoromethyl ) phenyl) oxazole -4- carboxylate  (22d)

R _f = 0.38 (hexane / Et ₂ O = 2: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.32 (s, 1H), 8.24 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). LRMS (ESI) m / z 286.0 [M + H] ⁺ and 308.1 [M + Na] ⁺ .

(5) Ethyl 2- (4- methoxyphenyl ) oxazole -4- carboxylate  (22e)

R _f = 0.13 (hexane / Et ₂ O = 2: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.24 (s, 1H), 8.06 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 4.43 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). LRMS (ESI) m / z 247.7 [M + H] ⁺ and 269.9 [M + Na] ⁺ .

(C) intermediate ethyl 2-aryl-5- via Heck reaction aryloxazole -4- carboxylate  Derivative synthesis method

(1) 22b (192 mg, 0.8 mmol), 2- iodonitrobenzene (398 mg, 1.6 mmol, 2.0 eq.), Palladium acetate (11.2 mg, 0.05 mmol, 0.06 eq.), Triphenylphosphine (21 A mixture of mg, 0.08 mmol, 0.1 eq.), cesium carbonate (651.6 mg, 2.0 mmol, 2.5 eq.) and DMF (4 mL) was flushed with nitrogen and heated at 140 ° C. for 3 hours, then the cooled mixture Was diluted with ethyl acetate, washed with water, brine, dried (MgSO ₄ ) and concentrated in vacuo. The product was purified by silica gel column chromatography (hexane / Et 2 O, 5: 1 to 1: 1, v / v) to give product 23b as yellow needle crystals (192 mg, 67%).

R _f = 0.35 (hexane / Et ₂ O = 1: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.20 (d, J = 8.1 Hz, 1H), 8.14 (q, J = 8.4 Hz, 1H), 8.18-8.09 (m, 1H), 7.83-7.65 (m , 3H), 7.19 (t, J = 8.7 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.3, 161.3, 160.6, 151.0, 148.5, 132.9, 132.6, 131.3, 130.2, 129.3, 129.2, 124.9, 122.6, 122.5, 122.5, 116.3, 116.0, 61.6, 14.0. LRMS (ESI) m / z 357.4 [M + H] ⁺ , 379.0 [M + Na] ⁺ , and 395.0 [M + K] ⁺ . HRMS (ESI) m / z calculated for C ₁₈ H ₁₄ FN ₂ O ₅ ⁺ [M + H] ⁺ : 357.0881; found: 357.0865.

(2) Ethyl 5- (2- nitrophenyl )-2- phenyloxazole -4- carboxylate  (23a)

R _f = 0.23 (hexane / Et ₂ O = 1: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.19 (d, J = 7.8 Hz, 1H), 8.16-8.08 (m, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.76-7.66 (m , 1H), 7.77 (d, J = 4.2 Hz, 2H), 7.55-7.43 (m, 3H), 4.32 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). LRMS (ESI) m / z 339.3 [M + H] ⁺ , 361.1 [M + Na] ⁺ , and 377.0 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₁₈ H ₁₄ N ₂ 0 ₅ Na ⁺ [M + Na] ⁺ : 361.0795; found: 361.0778.

(3) Ethyl 2- (4- chlorophenyl ) -5- (2- nitrophenyl ) oxazole -4- carboxylate  (23c)

R _f = 0.30 (hexane / Et ₂ O = 1: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.18 (d, J = 8.1 Hz, 1H), 8.05 (dd, J = 4.2 and 10.1 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.81-7.65 (m, 3H), 7.46 (d, J = 8.7 Hz, 1H), 7.46 (dd, J = 4.2 and 9.3 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 1.26 (t , J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 161.2, 160.5, 151.1, 148.5, 137.6, 132.8, 132.6, 131.3, 130.3, 129.2, 128.6, 124.9, 124.6, 122.6, 61.6, 29.7, 14.0. LRMS (ESI) m / z 373.1 [M + H] ⁺ , 395.0 [M + Na] ⁺ , and 411.0 [M + k] ⁺ . HRMS (ESI) m / z calculated for C ₁₈ H ₁₄ ClN ₂ O ₅ ⁺ [M + H] ⁺ : 373.0586; found: 373.0589.

(4) Ethyl 5- (2- nitrophenyl ) -2- (4- ( trifluoromethyl ) phenyl) oxazole -4- carb  oxylate (23d)

R _f = 0.20 (hexane / Et ₂ O = 1: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.24 (d, J = 8.1 Hz, 2H), 8.21 (d, J = 10.5 Hz, 1H), 7.86-7.68 (m, 5H), 4.32 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.1.1, 159.9, 151.7, 148.5, 133.0, 132.6, 127.3, 126.0, 125.9, 124.9, 61.8, 14.0. LRMS (ESI) m / z 407.0 [M + H] ⁺ , 428.7 [M + Na] ⁺ , and 445.3 [M + K] ⁺ . HRMS (ESI) m / z calculated for C ₁₈ H ₁₄ F ₃ N ₂ O ₅ ⁺ [M + H] ⁺ : 407.0849; found: 407.0809.

(5) Ethyl 2- (4- methoxyphenyl ) -5- (2- nitrophenyl ) oxazole -4- carboxylate  (23e)

R _f = 0.20 (hexane / Et ₂ O = 1: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.18 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.82-7.64 (m, 3H), 7.00 (t, J = 9.0 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 162.1, 161.5, 161.5, 150.4, 148.5, 132.8, 132.6, 131.1, 130.0, 128.8, 124.8, 122.8, 118.8, 114.3, 61.5, 55.5, 29.7, 14.1. LRMS (ESI) m / z 369.1 [M + H] ⁺ , 391.1 [M + Na] ⁺ , and 407.1 [M + K] ⁺ . HRMS (ESI) m / z calculated for C ₁₉ H ₁₇ N ₂ O ₆ ⁺ [M + H] ⁺ : 369.1081; found: 369.1090.

(d) intermediates through hydrogenation Amine  Derivative synthesis method

(1) Ethyl 5- (2- aminophenyl ) -2- (4- fluorophenyl ) oxazole -4- carboxylate  (24b)

A palladium catalyst was added to a solution of compound 23b (192 mg, 0.54 mmol) and MeOH (15 mL), and stirred for 1 hour in a hydrogen (50 psi) atmosphere. The reaction mixture was filtered through a celite bed and then the volatiles were reduced to remove to give 4a (145 mg, 82%) as a yellow solid.

R _f = 0.30 (hexane / Et ₂ O = 1: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.18-8.07 (m, 1H), 8.12 (q, J = 8.4 Hz, 1H), 7.43 (dd, J = 1.2 and 7.8 Hz, 1H), 7.29 (td , J = 8.1 and 1.5 Hz, 1H), 7.22-7.08 (m, 1H), 7.16 (t, J = 8.4 Hz, 1H), 6.84 (td, J = 7.8 and 1.2 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 4.16 (bs, 2H), 1.34 (t, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.2, 162.8, 162.1, 159.8, 154.4, 145.7, 131.8, 131.6, 129.8, 129.1, 129.0, 122.8, 122.8, 118.2, 116.7, 116.3, 116.0, 112.7, 61.5, 14.2. LRMS (ESI) m / z 327.1 [M + H] ⁺ and 349.1 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₁₈ H ₁₆ FN ₂ O ₃ ⁺ [M + H] ⁺ : 327.1139; found: 327.1133.

(2) Ethyl 5- (2- aminophenyl )-2- phenyloxazole -4- carboxylate  (24a)

R _f = 0.40 (hexane / Et ₂ O = 1: 2, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.22-8.11 (m, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.54-7.41 (m, 4H), 7.31 (td, J = 8.7 and 1.5 Hz, 1H), 6.87 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 4.25 (bs, 2H), 1.38 (t, J = 7.2 Hz, 3H). LRMS (ESI) m / z 309.3 [M + H] ⁺ , 331.2 [M + Na] ⁺ , and 347.0 [M + K] ⁺ . HRMS (ESI) m / z calculated for C ₁₈ H ₁₆ N ₂ O ₃ Na ⁺ [M + Na] ⁺ : 331.1053; found: 331.1051.

(3) Ethyl 5- (2- aminophenyl ) -2- (4- chlorophenyl ) oxazole -4- carboxylate  (24c)

R _f = 0.23 (hexane / Et ₂ O = 1: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.20 (d, J = 8.1 Hz, 1H), 8.14 (dd, J = 5.4 and 8.9 Hz, 2H), 7.83-7.65 (m, 3H), 7.19 (t , J = 8.7 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.3, 161.3, 160.6, 151.0, 148.5, 132.9, 132.6, 131.3, 130.2, 129.3, 129.2, 124.9, 122.6, 122.5, 122.5, 116.3, 116.0, 61.6, 14.0. LRMS (ESI) m / z 343.1 [M + H] ⁺ , 365.1 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₁₈ H 1 ₁₅ ClN ₂ O ₃ Na ⁺ [M + Na] ⁺ : 365.0663; found: 365.0678

(4) Ethyl 5- (2- aminophenyl ) -2- (4- ( trifluoromethyl ) phenyl) oxazole -4-car boxylate (24d)

R _f = 0.29 (CH ₂ Cl ₂ -MeOH = 20: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.25 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.31 ( t, J = 7.8 Hz, 1H), 6.86 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.17 (s, 2H), 1.29 (t, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 162.0, 159.2, 155.1, 132.0, 131.6, 127.1, 126.0, 125.9, 118.2, 116.9, 112.4, 61.7, 14.2. LRMS (ESI) m / z 356.8 [M + H] ⁺ and 398.9 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₁₈ H ₁₆ F ₃ N ₂ O ₃ ⁺ [M + Na] ⁺ : 377.1108; found: 377.1094.

(5) Ethyl 5- (2- aminophenyl ) -2- (4- methoxyphenyl ) oxazole -4- carboxylat  e (24e)

R _f = 0.28 (CH ₂ Cl ₂ -MeOH = 20: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.07 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.28 (t, J = 8.1 Hz, 2H), 6.98 ( d, J = 8.7 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 4.18 (bs, 2H), 1.34 (t, J = 7.2 Hz, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 162.8, 162.3, 157.8, 151.9, 138.4, 130.2, 129.3, 122.7, 121.6, 119.1, 115.4, 114.4, 111.6, 61.4, 55.4, 14.2. LRMS (ESI) m / z 339.1 [M + H] ⁺ and 361.1 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₁₉ H ₁₉ N ₂ O ₄ ⁺ [M + H] ⁺ : 339.1339; found: 339.1452.

(e) through a cyclization reaction Oxazoloquinolinone  Derivative synthesis method

(1) 2- (4-fluorophenyl) oxazolo [4,5-c] quinolin -4 (5H) -one (25b)

After heating the reflux mixture of 24b (95 mg, 0.27 mmol), DME (7 mL) and 2 M potassium carbonate solution (0.5 mL, 1.0 mmol) for 12 hours, the solids were collected by filtration and washed with cold EtOH. Drying in vacuo then gave 5a (45 mg, 60%).

R _f = 0.18 (CH ₂ Cl ₂ -MeOH = 1: 1, v / v). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.19 (bs, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.35 (d, J = 7.2 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 6.47 (t, J = 7.8 Hz, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.3, 161.3, 160.6, 151.0, 148.5, 132.9, 132.6, 131.3, 130.2, 129.3, 129.2, 124.9, 122.6, 122.5, 122.5, 116.3, 116.0, 61.6, 14.0. LRMS (ESI) m / z 302.7 [M + Na] ⁺ and 318.8 [M + K] ⁺ . HRMS (ESI) m / z calculated for C ₁₆ H ₁₀ FN ₂ O ₂ ⁺ [M + H] ⁺ : 281.0721; found: 281.0713.

(2) 2- Phenyloxazolo [4,5-c] quinolin -4 (5H) -one (25a)

R _f = 0.30 (CH ₂ Cl ₂ -MeOH = 20: 1, v / v). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 12.08 (bs, 1H), 8.29-8.18 (m, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.72-7.56 (m, 4H) , 7.52 (d, J = 8.1 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.3, 161.3, 160.6, 151.0, 148.5, 132.9, 132.6, 131.3, 130.2, 129.3, 129.2, 124.9, 122.6, 122.5, 122.5, 116.3, 116.0, 61.6, 14.0. LRMS (ESI) m / z 262.8 [M + H] ⁺ , 285.2 [M + Na] ⁺ , and 300.6 [M + K] ⁺ . HRMS (ESI) m / z calculated for C ₁₆ H ₁₁ N ₂ O ₂ ⁺ [M + H] ⁺ : 263.0815; found: 263.0845.

(3) 2- (4-Chlorophenyl) oxazolo [4,5-c] quinolin -4 (5H) -one (25c)

R _f = 0.32 (CH ₂ Cl ₂ -MeOH = 20: 1, v / v). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.24 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 7.5 Hz, 1H), 7.02 (t, J = 8.7 Hz, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 8.4 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.3, 161.3, 160.6, 151.0, 148.5, 132.9, 132.6, 131.3, 130.2, 129.3, 129.2, 124.9, 122.6, 122.5, 122.5, 116.3, 116.0, 61.6, 14.0. LRMS (ESI) m / z 335.2 [M + K] ⁺ . HRMS (ESI) m / z calculated for C ₁₆ H ₉ ClN ₂ O ₂ Na ⁺ [M + Na] ⁺ : 319.0245; found: 319.0276.

(4) 2- (4- (Trifluoromethyl) phenyl) oxazolo [4,5-c] quinolin -4 (5H) -one (25d)

R _f = 0.38 (CH ₂ Cl ₂ -MeOH = 20: 1, v / v). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.44 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.3, 161.3, 160.6, 151.0, 148.5, 132.9, 132.6, 131.3, 130.2, 129.3, 129.2, 124.9, 122.6, 122.5, 122.5, 116.3, 116.0, 61.6, 14.0. LRMS (ESI) m / z 353.5 [M + Na] ⁺ and 369.0 [M + K] ⁺ . HRMS (ESI) m / z calculated for C ₁₇ H ₁₀ F ₃ N ₂ O ₂ ⁺ [M + H] ⁺ : 331.0689; found: 331.0682.

(5) 2- (4-Methoxyphenyl) oxazolo [4,5-c] quinolin -4 (5H) -one (25e)

R _f = 0.28 (CH ₂ Cl ₂ -MeOH = 20: 1, v / v). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 11.18 (bs, 1H), 7.38-7.31 (m, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.19 (dd, J = 1.2 and 8.1 Hz, 1H), 6.76 (td, J = 8.4 and 1.5 Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H), 6.53 (td, J = 8.1 and 1.2 Hz, 1H), 6.41-6.33 ( m, 1H), 6.35 (d, J = 9.0 Hz, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.3, 161.3, 160.6, 151.0, 148.5, 132.9, 132.6, 131.3, 130.2, 129.3, 129.2, 124.9, 122.6, 122.5, 122.5, 116.3, 116.0, 61.6, 14.0. LRMS (ESI) m / z 293.1 [M + H] ⁺ , 314.9 [M + Na] ⁺ , and 331.0 [M + K] ⁺ . HRMS (ESI) m / z calculated for C ₁₇ H ₁₃ N ₂ O ₃ ⁺ [M + H] ⁺ : 293.0921; found: 293.0919.

(f) through an alkylation reaction Oxazoloquinolinone  Derivative final compound synthesis method

(1) 5- (2- ( dimethylamino ) ethyl) -2- (4-fluorophenyl) oxazolo [4,5-c] quinolin  -4 (5H) -one (3)

Compound 25b (43 mg, 0.153 mmol), 2-bromo-N, N-dimethylethanaminehydrobromide (80 mg, 0.31 mmol, 1.2 eq.), Potassium carbonate (63 mg, 0.46 mmol, 3.0 eq.) DMF (5 mL) was added, stirred at 130 ° C. for 3 hours, cooled to room temperature, then the solvent was removed in vacuo, and Et 2 O-MeOH (10: 1 to 3: 1, v / v) was added to the eluent. Purification by silica gel column chromatography was used to obtain [Formula 3].

Yield: 39%. R _f = 0.15 (EtO ₂ -MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.33-8.22 (m, 1H), 8.29 (dd, J = 5.4 and 8.7 Hz, 1H), 8.03 (dd, J = 1.5 and 8.0 Hz, 1H), 7.64 (td, J = 7.2 and 1.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 6.9 Hz, 1H), 7.22 (t, J = 8.4 Hz, 1H), 7.27 -7.16 (m, 1H), 4.58 (t, J = 7.8 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H), 2.41 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.5, 163.1, 161.7, 157.3, 152.3, 130.5, 129.8, 129.7, 129.6, 122.8, 122.8, 121.9, 116.4, 116.1, 115.4, 111.6, 56.3, 45.9, 40.8, 29.7, 22.7. LRMS (ESI) m / z 352.2 [M + H] ⁺ and 374.0 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₁₈ H ₁₉ FN ₃ O ₂ ⁺ [M + H] ⁺ : 352.1456; found: 352.1496.

(2) 5- (2- ( dimethylamino ) ethyl) -2- phenyloxazolo [4,5-c] quinolin -4 (5H) -one (2)

Yield: 39%. R _f = 0.25 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.34-8.27 (m, 2H), 8.07 (dd, J = 1.5 and 7.8 Hz, 1H), 7.69-7.51 (m, 5H), 7.38 (td, J = 7.2 and 1.2 Hz, 1H), 4.59 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 2.41 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 162.6, 157.4, 152.3, 137.9, 131.6, 130.5, 130.0, 129.0, 127.4, 126.5, 122.6, 122.0, 115.4, 111.8, 56.3, 45.9, 40.9. LRMS (ESI) m / z 333.4 [M + H] ⁺ and 355.3 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₂₀ H ₂₀ N ₃ 0 ₂ ⁺ [M + H] ⁺ : 334.1550; found: 334.1557.

(3) 2- (4- chlorophenyl ) -5- (2- (dimethylamino) ethyl) oxazolo [4,5-c] quinolin  -4 (5H) -one (4)

Yield: 26%. R _f = 0.17 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.24 (d, J = 8.7 Hz, 2H), 8.04 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.68 ( td, J = 7.5 and 1.5 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H), 4.43 (t, J = 5.1 Hz, 2H), 2.86 ( t, J = 5.1 Hz, 2H), 2.41 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 151.6, 138.1, 136.9, 130.6, 129.4, 129.0, 128.7, 127.5, 123.5, 121.44, 113.7, 109.5, 57.3, 53.4, 45.8, 29.7. LRMS (ESI) m / z 368.0 [M + H] ⁺ and 390.2 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₂₀ H ₁₉ ClN ₃ O ₂ ⁺ [M + H] ⁺ : 368.1160; found: 368.1202.

(4) 5- (2- ( dimethylamino ) ethyl) -2- (4- (trifluoromethyl) phenyl) oxazolo [4,5 -c] quinolin-4 (5H) -one (5)

Yield: 37%. R _f = 0.13 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.43 (d, J = 8.1 Hz, 2H), 8.09 (dd, J = 1.2 and 7.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.68 (dddd, J = 1.5, 7.2, and 8.7 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.41 (td, J = 7.8 and 0.9 Hz, 1H), 4.60 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 7.8 Hz, 2H), 2.42 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 161.0, 157.3, 152.8, 138.1, 131.0, 127.7, 126.1, 126.1, 126.0, 126.0, 122.8, 122.1, 115.5, 111.5, 56.3, 45.9, 37.6. LRMS (ESI) m / z 402.1 [M + H] ⁺ and 424.1 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₂₁ H ₁₉ F ₃ N ₃ O ₂ ⁺ [M + H] ⁺ : 402.1424; found: 402.1426.

(5) 5- (2- ( dimethylamino ) ethyl) -2- (4-methoxyphenyl) oxazolo [4,5-c] quinol  in-4 (5H) -one (6)

Yield: 18%. R _f = 0.08 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.24 (d, J = 9.0 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.64-7.60 (m, 2H), 7.40-7.33 (m , 1H), 7.04 (d, J = 8.7 Hz, 2H), 4.62 (t, J = 7.5 Hz, 2H), 3.09 (s, 3H), 2.72 (t, J = 7.8 Hz, 2H), 2.44 (s , 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 162.8, 162.4, 157.5, 152.0, 137.6, 130.1, 129.9, 129.4, 122.6, 121.8, 119.1, 115.4, 114.4, 111.8, 56.0, 55.5, 45.6, 40.5, 29.7. LRMS (ESI) m / z 364.1 [M + H] ⁺ and 387.1 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₂₁ H ₂₂ N ₃ O ₃ ⁺ [M + H] ⁺ : 364.1656; found: 364.1694.

(6) N, N - dimethyl -2-((2- phenyloxazolo [4,5-c] quinolin -4- yl ) oxy) ethanamine (7)

Yield: 9%. R _f = 0.36 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.38-8.31 (m, 2H), 8.16 (dd, J = 0.9 and 8.1 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.66 (td , J = 7.2 and 1.5 Hz, 1H), 7.59-7.48 (m, 4H), 4.84 (t, J = 6.0 Hz, 2H), 2.94 (t, J = 6.0 Hz, 1H), 2.42 (s, 6H) ; ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 163.0, 154.7, 153.9, 144.2, 131.6, 129.1, 129.0, 127.9, 127.6, 126.7, 126.5, 124.7, 120.3, 114.7, 64.1, 57.9, 45.9. LRMS (ESI) m / z 333.9 [M + H] ⁺ and 356.9 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₂₀ H ₂₀ N ₃ 0 ₂ ⁺ [M + H] ⁺ : 334.1550; found: 334.1552.

(7) 2-((2- (4-fluorophenyl) oxazolo [4,5-c] quinolin -4- yl ) oxy)- N, N - dimethyl  ethanamine (8)

Yield: 9%. R _f = 0.30 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.41-8.28 (m, 1H), 8.29 (dd, J = 5.4 and 9.0 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.96 (d , J = 8.1 Hz, 1H), 7.67 (ddd, J = 1.5, 7.1, and 8.4 Hz, 1H), 7.52 (td, J = 8.0 and 0.9 Hz, 1H), 7.29-7.18 (m, 2H), 4.83 (t, J = 6.0 Hz, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.41 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.6, 163.2, 161.8, 154.6, 153.9, 144.2, 129.9, 129.8, 128.0, 126.4, 124.8, 123.0, 123.0, 120.2, 116.4, 116.1, 114.6, 64.1, 57.9, 45.8, 29.7. LRMS (ESI) m / z 352.2 [M + H] ⁺ and 374.0 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₂₀ H ₁₉ FN ₃ O ₂ ⁺ [M + H] ⁺ : 352.1456; found: 352.1498.

(8) 2-((2- (4-chlorophenyl) oxazolo [4,5-c] quinolin -4- yl ) oxy)- N, N - dimethyl  ethanamine (9)

Yield: 8%. R _f = 0.28 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.27 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.67 ( t, J = 7.5 Hz, 1H), 7.53 (d, J = 8.1 Hz, 3H), 4.84 (t, J = 5.1 Hz, 2H), 2.94 (t, J = 5.1 Hz, 2H), 2.42 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 161.7, 154.6, 153.9, 144.3, 138.0, 129.4, 129.3, 128.4, 128.0, 126.4, 125.2, 124.8, 120.2, 114.6, 64.8, 57.9, 53.4, 45.8, 31.9. LRMS (ESI) m / z 368.2 [M + H] ⁺ and 390.2 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₂₀ H ₁₉ ClN ₃ O ₂ ⁺ [M + H] ⁺ : 368.1160; found: 368.1195.

(9) N, N - dimethyl -2-((2- (4- (trifluoromethyl) phenyl) oxazolo [4,5- c] quinolin -4- yl ) oxy) ethanamine  10

Yield: 10%. R _f = 0.38 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.47 (d, J = 8.1 Hz, 2H), 8.18 (d, J = 7.8 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.82 ( d, J = 8.4 Hz, 2H), 7.69 (td, J = 7.2 and 1.5 Hz, 1H), 7.54 (td, J = 7.2 and 1.2 Hz, 1H), 4.49 (t, J = 6.3 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.42 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.1, 154.7, 154.1, 144.4, 129.8, 129.5, 128.0, 127.8, 126.4, 126.0, 126.0, 124.9, 120.4, 114.5, 64.2, 59.6, 45.9. LRMS (ESI) m / z 402.1 [M + H] ⁺ and 424.1 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₂₁ H ₁₉ F ₃ N ₃ O ₂ ⁺ [M + H] ⁺ : 402.1424; found: 402.1437.

(10) 2-((2- (4-methoxyphenyl) oxazolo [4,5-c] quinolin -4- yl ) oxy)- N, N - dimet  hylethanamine (11)

Yield: 15%. R _f = 0.18 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.26 (d, J = 8.1 Hz, 2H), 8.16 (d, J = 6.3 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.66 ( dd, J = 6.9 and 14.3 Hz, 1H), 7.54 (dd, J = 7.8 and 16.2 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 4.86 (t, J = 6.3 Hz, 2H), 3.91 (s, 3 H), 3.01 (t, J = 6.3 Hz, 2H), 2.47 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 163.0, 162.5, 154.6, 153.6, 144.0, 129.4, 128.8, 127.9, 126.5, 124.7, 120.2, 119.2, 114.8, 114.5, 63.7, 57.8, 55.5, 45.6, 30.4. LRMS (ESI) m / z 364.5 [M + H] ⁺ and 387.5 [M + Na] ⁺ . HRMS (ESI) m / z calculated for C ₂₁ H ₂₂ N ₃ O ₃ ⁺ [M + H] ⁺ : 364.1656; found: 364.1693.

(11) 5- (2- ( diethylamino ) ethyl) -2- (4-fluorophenyl) oxazolo [4,5-c] quinolin-4 (5H) -one (12)

Yield: 14%. R _f = 0.39 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.35-8.26 (m, 1H), 8.30 (dd, J = 5.4 and 8.7 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.66-7.59 (m, 2H), 7.43-7.34 (m, 1H), 7.22 (t, J = 8.7 Hz, 2H), 4.55 (t, J = 7.8 Hz, 2H), 2.79 (t, J = 7.8 Hz, 2H) , 2.68 (dd, J = 7.2 and 14.4 Hz, 4H), 1.09 (t, J = 7.2 Hz, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.5, 163.2, 161.7, 157.4, 152.3, 138.0, 130.5, 129.8, 129.7, 129.6, 122.8, 122.8, 122.6, 121.8, 116.4, 116.1, 115.6, 111.6, 50.0, 47.6, 41.2, 12.0. LRMS (ESI) m / z 380.3 [M + H] ⁺ . HRMS (ESI) m / z calculated for C ₂₂ H ₂₃ FN ₃ O ₂ ⁺ [M + H] ⁺ : 380.1769; found: 380.1817.

(12) N, N -diethyl-2-((2- (4-fluorophenyl) oxazolo [4,5-c] quinolin -4- yl ) oxy) ethanamine (13)

Yield: 8%. R _f = 0.51 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.38-8.31 (m, 1H), 8.35 (dd, J = 5.4 and 9.0 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.96 (d , J = 8.4 Hz, 1H), 7.66 (ddd, J = 1.5, 7.1, and 8.4 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.28-7.19 (m, 2H), 4.81 (t , J = 6.9 Hz, 2H), 3.06 (t, J = 6.9 Hz, 2H), 2.72 (dd, J = 7.2 and 14.4 Hz, 4H), 1.14 (t, J = 7.2 Hz, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ ppm 166.6, 163.2, 161.8, 154.6, 153.8, 144.2, 129.9, 129.8, 129.1, 128.0, 126.4, 124.7, 123.0, 123.0, 120.2, 116.5, 116.2, 114.6, 64.2, 51.0, 47.7, 29.7, 11.8. LRMS (ESI) m / z 380.3 [M + H] ⁺ . HRMS (ESI) m / z calculated for C ₂₂ H ₂₃ FN ₃ O ₂ ⁺ [M + H] ⁺ : 380.1769; found: 380.1814.

(13) 5- (2- ( diethylamino ) ethyl) -2- (4- ( trifluoromethyl ) phenyl) oxazolo  [4,5-c] quinolin-4 (5H) -one (14)

Yield: 27%. R _f = 0.39 (Et ₂ O-MeOH = 5: 1, v / v). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.44 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.71-7.60 (m, 2H), 7.70 (t, J = 7.8 Hz, 1H), 4.56 (t, J = 7.8 Hz, 2H), 2.80 (t, J = 8.1 Hz, 2H), 2.69 (dd, J = 7.2 and 14.4 Hz, 4H), 1.09 (t, J = 7.2 Hz, 6H).

(14) N, N -diethyl-2-((2- (4- (trifluoromethyl) phenyl) oxazolo [4,5- c] quinolin -4- yl ) oxy) ethanamine  (15)

Yield: 50%. R _f = 0.51 (Et ₂ O-MeOH = 5: 1, v / v). 1 HNMR (300 MHz, CDCl ₃ ) δ ppm 8.45 (d, J = 8.1 Hz, 2H), 8.15 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.68 (ddd, J = 1.5, 7.1, and 8.4 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 4.81 (t, J = 6.9 Hz, 2H), 3.06 ( t, J = 7.2 Hz, 2H), 2.72 (dd, J = 7.2 and 14.4 Hz, 4H), 1.09 (t, J = 7.2 Hz, 6H).

Experimental Example  One

As can be seen in Korean Patent Application No. 10-2018-0001019 (2018.01.04.), The inventor of the present invention prior to the present application, IL-33 inhibition against the oxazoloquinolinone derivative compounds according to the present invention Evaluation of the inhibitory effect of IL-6 secretion was performed and the results were confirmed. The oxazoloquinolinone derivatives according to the present invention bind IL-33 and ST-2, which play a key role in inflammatory processes. Or it was confirmed that effectively inhibits the binding between the cytokine TSLP and TSLP receptor.

Therefore, according to the present invention, it is expected that by inhibiting the signal transduction mediated by IL-33 or TSLP, it is possible to fundamentally treat depressive disorders and stress-related diseases caused by inflammatory processes, and also degenerative brain diseases.

Experimental Example  2: according to the present invention Oxazoloquinolinone  Compound [Formula 10] (KB- 1518) LPS antidepressant in -mediated depression in animal models Behavioral Analysis of Efficacy

end. Materials and methods

(1) Adult male C57BL / 6 mice were used. Mice were housed in a cage per breeding cage and fed freely with food and water under a 12-hour light cycle (lights up at 8 o'clock). Adapted to the environment during the week, all experimental procedures were performed according to the guidelines of Korea University.

(2) E. coli lipopolysaccharide (LPS, lipopolysaccharide; O26: B6, Sigma-Aldrich L3755) dissolved in sterile phosphate buffered saline was injected intraperitoneally in a volume of 0.1 mL (5 μg / mouse).

After dissolving the compound of Formula 10 according to the present invention in a DMSO: PBS (2: 8 ratio) solution and adapting the 7-week-old rat to the environment, the 8-week-old compound of Formula 10 was administered at 10 mg / kg. After intraperitoneal injection, 5 μg of LPS was injected intraperitoneally after 2 hours, followed by TST (tail suspension test), OFT (open field test), and FST (forced swim test) 2 hours later. It proceeded to, and the results are shown in Figure 1 below.

I. Statistical analysis

Statistical analysis was performed using computer software (PASW Statistics 18; SPSS Inc., Chicago, IL), and data were analyzed using two independent sample t-tests (Student t-test). , All results are expressed as mean ± SEM. In addition, all statistics were 2-tailed and analyzed with significant results below p <0.05.

All. Depression-related Behavioral Assessment of Mice

(1) Tail suspension test (TST)

In order to confirm the antidepressant effect of the oxazoloquinolinone derivative compound according to the present invention, the mouse-related depression was observed and a mouse tail suspension test known as a method of confirming the antidepressant effect was performed.

The TST device divided the four compartments into non-transparent compartments and made of non-gloss acrylic. Each mouse was suspended in a position where it was unable to escape by the tail or grab the surface closer using tape individually for 6 minutes. Immobility was defined as the absence of limb movement, with no movement, and evaluated by measuring the time of inactivity (float time) during the last 4 minutes except the first 2 minutes of the total 6 minutes of testing.

(2) Open field test (OFT)

In order to confirm whether the antidepressant effect of the oxazoloquinolinone derivative compound according to the present invention is due to a simple change in motility, an open space test of a mouse known as a method of confirming the antidepressant effect was performed.

The mouse was placed in the corner of an open field chamber (45 cm wide x 45 cm deep x 40 cm high) and behavior was analyzed by recording the light block produced by the mouse. Mouse activity was recorded as the total distance traveled and the time spent identifying the central area of the chamber (13.5 × 13.5 cm 2).

(3) forced swim test (FST)

In order to confirm the antidepressant effect of the oxazoloquinolinone derivative compound according to the present invention, the depressive-related behavior of the mouse was observed, and a forced swimming test known as a method of confirming the antidepressant effect was performed.

Partially filled with water at 24-25 ° C in a clean cylinder (12 cm in diameter and 24 cm in height), and the depth of the water can measure the movement or floatability of swimming or climbing without the mouse's hind legs or tail touching the bottom of the cylinder. It was set to. Mouse behavior was recorded using an infrared camera for 6 minutes, and passivity was passively floating in the water, defined as the minimum movement required to keep the head above the water. During the last 4 minutes except for the first 2 minutes of the total 6 minutes of the test was measured by measuring the time (floating time) in the absence of motion, and by additionally measuring the swimming time to climb the cylinder wall of the swimming method.

(4) The depression-related behavioral evaluation of the mouse was performed according to a known procedure, formula 10 (KB1518) was 240 minutes, and LPS was 120 minutes before TST (FIG. 1A). The three tests, TST, OFT and FST, were performed in one session (TST → 6 min break in cage → OFT → 6 min break → FST). The FST was performed last because it was considered to be the most stressful and likely to affect subsequent tests. In contrast, TST appeared positive and had little effect on subsequent behavior of mice.

la. In conclusion, as can be seen from the results shown in Figure 1, it can be seen that pretreatment of the oxazoloquinolinone derivative compound according to the present invention attenuates the behavior related to depression in TST behavior evaluation.

The inventors of the present invention, KB1518 mice 120 minutes before LPS injection to confirm whether the depression model by LPS injection was attenuated by treatment of oxazoloquinolinone derivative compound (KB1518) according to the present invention confirmed the IL-33 inhibitory properties Behavioral evaluation was investigated after administration of the mice, and mice pretreated with KB1518 showed reduced immobility time in TST evaluation (FIG. 1B).

Previous reports have shown that mice injected with LPS (O26: B6) show depressive behavior two hours after LPS injection [Pharmacol. Biochem. Behav. 2005. 81: 688-693], KB1518 was found to inhibit LPS-induced depression-related behavior.

In addition, the FST results did not show a significant difference in immobility time, but KB1518 treated mice were also more active in the swimming approach to climb the wall in FST evaluation. (FIG. 1D, right panel). Indeed, norepinephrine-targeted antidepressant treatments are known to selectively increase the swimming way to climb walls in FST [Eur. J. Pharmacol. 2009. 616: 128-133; Biol. Psychiatry. 2002. 51: 882-889].

Therefore, KB1518 may be used as an antidepressant or stress mitigating agent as it alleviates major depression and stress related behaviors in animal models of LPS-induced depression.

Claims (5)

A pharmaceutical composition for preventing or treating depression and stress-related diseases containing an oxazoloquinolinone derivative represented by the following [Formula 1a] or [Formula 1b] as an active ingredient and a pharmaceutically acceptable carrier:
[Formula 1a]

[Formula 1b]

In [Formula 1a] and [Formula 1b],
R ₁ and R ₂ is the same as or different from each other, and each independently an alkyl group having 1 to 10 carbon atoms, and any one selected from the following [Formula 1]
[Formula 1]
-Z-alkyl group
In [Formula 1], Z is a hetero atom selected from O, S or N, or-(CH ₂ ) _m- (wherein m is an integer of 0 to 5),
X and Y are each independently selected from hydrogen, halogen group, hydroxyl group, amino group, nitro group, cyano group, halogenated alkyl group having 1 to 10 carbon atoms, CO-R ', NHR', NR'R ', NHCOR' and COOR ' (Wherein R 'is an alkyl group having 1 to 10 carbon atoms),
p is an integer of 0-4, q is an integer of 0-5, and when said p and q are multiple, some X and some Y are each the same or different. The method of claim 1,
The oxazoloquinolinone derivative represented by the above [Formula 1a] or [Formula 1b] is any one selected from the derivatives represented by the following [Formula 2] to [Formula 15] of depression and stress-related diseases Prophylactic or therapeutic pharmaceutical compositions:
[Formula 2] [Formula 3]

[Formula 4] [Formula 5]

[Formula 6] [Formula 7]

[Formula 8] [Formula 9]

[Formula 10] [Formula 11]

[Formula 12] [Formula 13]

[Formula 14] [Formula 15]

The method of claim 1,
The composition is a pharmaceutical composition for preventing or treating depression and stress-related diseases, characterized in that for controlling intracellular signal transduction by TSLP and IL-33. The method of claim 1,
The composition is a pharmaceutical composition for the prevention or treatment of depression and stress-related diseases characterized in that it inhibits the binding between the cytokine thymic stromal lymphopoietin (TSLP) and the TSLP receptor or inhibits the binding between the cytokine IL-33 and ST-2 The method of claim 1,
The stress-related disease is a depression, post-traumatic stress disorder, or a degenerative brain disease including Alzheimer's disease and Parkinson's disease, characterized in that the disease selected from the pharmaceutical composition for the prevention or treatment of depression and stress-related diseases.

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